A randomized clinical pharmacokinetic trial of Tenofovir in blood, plasma and urine in adults with perfect, moderate and low PrEP adherence: the TARGET study

Tim R Cressey, Oraphan Siriprakaisil, Virat Klinbuayaem, Justice Quame-Amaglo, Rachel W Kubiak, Pra-Ornsuda Sukrakanchana, Kanchana Than-In-At, Jared Baeten, Wasna Sirirungsi, Ratchada Cressey, Paul K Drain, Tim R Cressey, Oraphan Siriprakaisil, Virat Klinbuayaem, Justice Quame-Amaglo, Rachel W Kubiak, Pra-Ornsuda Sukrakanchana, Kanchana Than-In-At, Jared Baeten, Wasna Sirirungsi, Ratchada Cressey, Paul K Drain

Abstract

Background: Tenofovir disoproxil fumarate (TDF) is key component of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) for HIV, but existing tools to monitor drug adherence are often inaccurate. Detection of tenofovir (TFV) in accessible biological samples, such as fingerprick blood, urine or oral fluid samples could be a novel objective measure of recent TDF adherence. To measure TFV concentrations associated with different levels of TDF adherence, we designed a randomized clinical trial to assess the blood, urine and oral fluid concentrations of TFV in adults with perfect, moderate and low drug adherence.

Methods/design: A randomized, open-label, clinical pharmacokinetic study of tenofovir in healthy adult volunteers without HIV or Hepatitis B infection in Thailand. Consenting, eligible participants are randomized (1:1:1) among three groups to receive a controlled number of TDF (300 mg) doses in a combination pill with emtricitabine (FTC, 200 mg) for six weeks. Participants in Group 1 receive a single TDF/FTC tablet once daily (Perfect adherence); Group 2 receive a single TDF/FTC tablet 4 times/week (Moderate adherence); and Group 3 receive a single TDF/FTC tablet 2 times/week (Low adherence). Blood, plasma, urine and oral fluid samples are collected for drug measurement during three study phases: (i) initial 6-week treatment phase; (ii) intensive 24-h blood sampling phase after 6 weeks; (iii) 4-week washout phase. Thirty adults with evaluable pharmacokinetic samples (10 per group) will be enrolled [based on ensuring 25% precision in pharmacokinetic parameter estimates]. Pre-dose drug concentrations during the treatment phase will be descriptive and comparisons between groups performed using a Kruskal-Wallis test. A non-compartmental pharmacokinetic analysis will be performed on the intensive sampling data at Week 7 and the time course of TFV washout in the difference biological matrices will be reported based on the detected concentrations following drug cessation.

Discussion: The results of this randomized trial will define the target concentration thresholds of TFV in blood, urine and oral fluid that can distinguish between different levels of TDF adherence. Such adherence 'benchmarks' can be applied to real-time drug testing and novel point-of-care tests to identify individuals with poor PrEP or ART adherence.

Trial registration: ClinicalTrials.gov Identifier NCT03012607 .

Keywords: Antiretroviral treatment; HIV; Pre-exposure prophylaxis; Tenofovir; Thailand.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol and consent documents have been approved by Ethics Committees at the Institute for the Development of Human Research Protections at the Medical Sciences Department, Thai Ministry of Public Health; Sanpatong Hospital; Faculty of Associated Medical Sciences at Chiang Mai University, and the University of Washington Institutional Review Board in Seattle.

Consent for publication

Not applicable.

Competing interests

JB has served on an advisory board for Gilead Sciences Inc. and has previously received medications from Gilead Sciences to support the conducted of PrEP for HIV prevention studies. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study schema

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